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The kidney performs several major functions: it eliminates toxins produced by cellular or xenobiotic metabolism, regulates the homeostasis of the internal environment and plays a hormonal role, producing erythropoietin, calcitriol and renin. Maintaining the body's homeostasis (hydric, ionic [sodium, potassium, calcium, phosphorus, etc.] or acid-base balance) requires the successive action of plasma filtration, followed by reabsorption/secretion mechanisms, which take place in the various portions of the kidney's functional unit known as the nephron. The initial part of the nephron, the glomerulus, is the site of filtration, while the tubule, which collects the glomerular filtrate, is the site of reabsorption/secretion, leading to the composition of the final urine. It's important to understand how these different structures work, before tackling the various disorders that can affect the kidney., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Germinal center regulation pathways are often involved in lymphomagenesis and myelomagenesis. Most of the lymphomas (and multiple myeloma) derive from post-germinal center B-cells that have undergone somatic hypermutation and class switch recombination. Hence, B-cell clonal expansion can be responsible for the presence of a monoclonal component (immunoglobulin) of variable titer which, owing to physicochemical properties, can provoke pathologically defined entities of diseases. These diseases can affect any functional part of the kidney, by multiple mechanisms, either well known or not. The presence of renal deposition is influenced by germinal gene involved, immunoglobulin primary structure, post-translational modifications and microenvironmental interactions. The two ways immunoglobulin can cause kidney toxicity are (i) an excess of production (overcoming catabolism power by proximal tubule epithelial cells) with an excess of free light chains within the distal tubules and a subsequent risk of precipitation due to local physicochemical properties; (ii) by structural characteristics that predispose immunoglobulin to a renal disease (whatever their titer). The purpose of this manuscript is to review literature concerning the pathophysiology of renal toxicities of clonal immunoglobulin, from molecular B-cell expansion mechanisms to immunoglobulin renal toxicity., (Copyright © 2022 Société francophone de néphrologie, dialyse et transplantation. Published by Elsevier Masson SAS. All rights reserved.)

The SFBC working group aimed to deal with biological tests outside the French nomenclature that may be useful for the follow-up of dialysis patients. Our discussion was divided into 3 parts: 1) evaluation of peritoneal membrane characteristics; 2) monitoring of renal replacement therapy using regional citrate anticoagulation; 3) estimation of residual renal function (RRF). International recommendations underline the importance of assessing peritoneal membrane characteristics for peritoneal dialysis prescription. This peritoneal equilibrium test requires the measurement in dialysate of the following parameters: glucose, urea, creatinine and sodium. As part of the monitoring of continuous renal replacement therapy using regional citrate anticoagulation, the determination of ionized calcium assay is essential according to national and international guidelines to ensure a balance between effective anticoagulation and appropriate calcium levels. Finally, the RRF plays a key role in the dialysis adequacy and patient survival. European and international recommendations highlight the potential interest of RRF in peritoneal dialysis and hemodialysis. The RRF corresponds to the mean of urinary urea and creatinine clearance, assessed from a urine collection with measurement of urinary urea.

The acid production of endogenous origin depends mainly on the metabolism of the food and varies with the nature of these. Of the order of 1mEq/kg/day for contemporary food in industrialized countries, it is reduced by more than one third among vegetarians and close to neutrality among vegans. The dietary acid load is eliminated by the normal kidneys, thus maintaining the acid-base equilibrium. In the setting of CKD, it will overflow the capacities of the nephrons, generating a retention of H+ ions, promoting subclinical acidosis. This tissue retention of H+ ions was confirmed by direct techniques in animal models and indirect techniques in humans. The systemic retention of H+ ions and the accompanying compensatory mechanisms have negative consequences on bone tissue, skeletal muscle, cardiovascular risk and renal function. In the animal, the substitution of casein (acid) by soy (alkaline) prevents metabolic acidosis and slows the progression of renal insufficiency. In man, various prospective studies have confirmed that the risk of renal insufficiency was positively correlated with the dietary acid load. Conversely, bicarbonate supplementation and/or a diet enriched with fruits and vegetables, have a favorable effect on renal insufficiency, including in subjects with normal bicarbonate. These results lead to reconsider the K/DOQI recommendations to correct acidosis when the bicarbonate level falls below 22mEq/L, since tissue retention of H+ ions and its negative consequences appear at higher or even normal levels of bicarbonates., (Copyright © 2017 Société francophone de néphrologie, dialyse et transplantation. Published by Elsevier Masson SAS. All rights reserved.)

Kidney plays an important role in glucose homeostasis, both in the post-absorptive and postprandial period. Kidney produces glucose by gluconeogenesis in the renal cortex and uses glucose for covering energy needs of the medulla. Kidney participates also to the reabsorption of filtered glucose in order the terminal urine was devoided of glucose, as long as blood glucose did not exceed 180mg/dL. Reabsorption of glucose is mediated by sodium-glucose cotransporters (SGLT1 et SGLT2) expressed in S1 and S3 segments of proximal tubule. SGLT2 is the main sodium-glucose cotransporter responsible for 90% of glucose reabsorption. In type 2 diabetics, renal gluconeogenesis and glucose utilisation are increased by 30%. Surprisingly, renal glucose reabsorption is increased, participating to worsening of hyperglycemia. This results from the increase in the renal threshhold of glucose reabsorption (220mg/dL) and from an overexpression of SGLT2 in response to hyperglycemia and of cytokine secretion. The administration of SGLT2 inhibitors to type 2 diabetic patients induced a decreased in the renal threshhold of glucose reabsorption (80mg/dL) and strongly reduced kidney glucose reabsorption. The inhibitors of SGLT2 are the only antidiabetic molecules able to correct the excessive renal glucose reabsorption in type 2 diabetics and thus to contribute, by an original mechanism, to the lowering of blood glucose level., (Copyright © 2017 Société francophone de néphrologie, dialyse et transplantation. Published by Elsevier Masson SAS. All rights reserved.)

Renal fibrosis represents the final stage of most chronic kidney diseases and contributes to the progressive and irreversible decline in kidney function with accumulation of extracellular matrix components in the renal parenchyma. The molecular mechanisms governing the renal fibrosis process are complex and remain poorly understood. Recently, the profibrotic role of several microRNAs (miRNAs) has been described in kidney fibrosis. MiRNAs are a new class of, small non-coding RNAs of about 20 nucleotides that act as gene expression negative regulators at the post-transcriptional level. Seminal studies have highlighted the potential importance of miRNA as new therapeutic targets and innovative diagnostic and/or prognostic biomarkers. This review summarizes recent scientific advances on the role played by miRNAs in kidney fibrogenesis and discusses potential clinical applications as well as future research directions., (Copyright © 2015 Association Société de néphrologie. Published by Elsevier SAS. All rights reserved.)

Canagliflozin is an inhibitor of sodium-glucose cotransporters type 2 (SGLT2) that are present in renal tubules. This specific insulin-independent mechanism promotes glucosuria, which results in a reduction in fasting and postprandial glycaemia and a decrease of glycated haemoglobin (HbA(1c)). Furthermore, canagliflozin promotes weight loss and lowers arterial (mainly systolic) blood pressure. Its efficacy is decreased in patients with renal insufficiency and the treatment should be stopped if estimated glomerular filtration rate is below 45 ml/min/1.73 m2. Both the efficacy and safety of canagliflozin have been investigated in 24 to 104-week controlled trials versus placebo or versus an active comparator (glimepiride or sitagliptin). The mean reduction in HbA(1c) averages 0.75% when added to other treatments, as compared to placebo. The 100 mg dose is as active as sitagliptin 100 mg while the 300 mg canagliflozin dose is even more efficacious. Adverse events are mostly mycotic genital infections and more rarely mild urinary tract infections. Caution is required in elderly patients and the risk of volume depletion should be checked (hypotension). Hypoglycaemia may occur only in patients already treated with an insulin-secreting agent or insulin. Canagliflozin is commercialized under the trade name Invokana, at the doses of 100 mg and 300 mg once daily, for the treatment of type 2 diabetes.

Thrombospondin-1 (TSP-1) is a 450-kDa matricellar glycoprotein. By its various domains, it can interact with various partners and exhibit anti-angiogenic, pro-apoptotic and immunomodulatory activities. TSP-1 is also a major endogenous activator of the pro-fibrotic growth factor TGF-β. In healthy adult renal parenchyma, TSP-1 expression is very scarce and limited to Bowman's capsule and interstitium. During nephropathies, many cell types can express or secrete TSP-1 (mesangial, endothelial, smooth muscle, tubular cells, podocytes and fibroblasts) depending on the nature of injury and the evolutive stage of the disease. Inhibition of the different domains of TSP-1 using specific antibodies or peptides, blockade of TSP-1 expression by antisense oligonucleotides and use of knock-out mice, allowed to identify the role of TSP-1 in various models of experimental nephropathy. All these studies demonstrated a deleterious effect of TSP-1 on renal repair by inducing TGF-β and fibrosis, decreasing VEGF and capillary density, and enhancing inflammatory cells recruitment. Thus, TSP-1 represents a potential therapeutic target for the management of chronic kidney diseases., (© 2013 médecine/sciences – Inserm.)

Calcitriol and analogs inhibit renin-angiotensin system, which has a pivotal role in glomerular and tubulo-interstitial damages and proteinuria, and inhibit NF-κB activation which is known to play an important role in renal diseases by promoting inflammation and fibrogenesis. Vitamin D presents interesting pleiotropic effects for the CKD patient (reduction of mortality, antiproteinuric effect and anti-inflammatory properties). "Native" vitamin D (cholecalciferol or ergocalciferol) administration in these patients also decrease parathyroid hormone levels. Native vitamin D administration in CKD patients is safe and does not lead to increased risk of vascular calcification, despite the known hypercalcemic and hyperphosphoremic properties of the molecule in its active form. Native vitamin D administration is not associated with an increased risk of renal stones, at pharmacological doses and without important concomitant administration of calcium salts. In the field of renal transplantation, experimental studies show that vitamin D analogs have a protective role against acute rejection but clinical studies remain mainly observational., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Aim: The antihypertensive effect of renal denervation in hypertensive patients is partially explained by increased tubular natriuresis. To study the possible contribution of the kallikrein-kinin system (KKS) to this natriuretic effect in rats, we measured kallikrein activity (KA) and bradykinin concentrations (BK) in plasma and tissues., Methods: To measure KA, we adapted and validated an enzymatic assay that cleaves para-nitroaniline (pNA) from the tripeptide H-D-Pro-Phe-Arg-pNA. The coefficients of variation (CV) within- and between-assays were less than 8% for plasma and tissue KA (plasma n=6 and 13; tissue n=4). Linear results for serially diluted samples confirmed the assay specificity. Tissue BK determinations were based on an established assay for plasma BK: tissue was homogenized and kinins extracted in ethanol, and BK was isolated by high-performance (HPLC) liquid chromatography and quantitated by radioimmunassay. Within- and between-assay CV for plasma BK were 18% (n=8 and n=35, respectively) and for BK in various tissues less than 16% (n=5-8)., Results: In male Wistar rats (n=3), plasma BK was 8.2 ± 6.6 fmol/mL (mean ± SD), and tissue BK (fmol/g) in 14 tested organs varied between brain (14 ± 3) and submaxillary gland (521 ± 315). Six days after left-sided unilateral renal denervation, left renal tissue BK (89 ± 9) was not different from right renal BK (75 ± 23). Similarly, KA was comparable in the two kidneys (left 18.0 ± 1.5, right 15.8 ± 1.4 μkat/g)., Conclusion: Any possible effect of unilateral renal denervation on the kidney's KKS would have to be bilateral., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Mitochondrial disorders are genetic defects of oxidative phosphorylation. Oxidative phosphorylation takes place in the mitochondrial inner membrane and consists of the oxidation of fuel molecules by oxygen and the concomitant energy transduction into ATP. The mitochondrial respiratory chain is a complex metabolic pathway. It is made of approximately 100 polypeptides, most of which are encoded in the nucleus whereas 13 are encoded in the mitochondria. Mitochondrial DNA is maternally inherited and its mutations are transmitted by the mother. During cell division, mitochondria are randomly partitioned in daughter cells. Therefore, in case normal and mutant DNA are present in the mother's cells, some lineage may have only mutant mitochondrial DNA or normal mitochondrial DNA while others may have both mutant and normal DNA, a condition named heteroplasmy. Renal involvement in mitochondrial cytopathies is rare. Patients most often present with a more or less complete de Toni-Debré-Fanconi syndrome. A few patients present with a nephrotic syndrome or with chronic tubulointerstitial nephritis. The investigation of patients with mitochondrial disorders include metabolic screening for abnormal oxidoreduction status in plasma, investigation of the mitochondrial respiratory chain, including polarographic and spectrophotometric studies, histopathologic studies and genetic studies., (Copyright © 2012. Published by Elsevier SAS.)

Extracellular content in magnesium represents about 1% of total body content, of which plasma magnesium is thus a poor reflect. Hypomagnesaemia is defined by a value lesser than 0.65mmol/L. Its incidence in hospitalized patients ranges between 10 and 15%. Identification of the physiopathology of hypomagnesaemia relies first upon concomitant measurement of plasma and urinary magnesium concentration. Daily magnesium excretion lesser than 1mmol/L or EFMg lesser than 1% sign extra renal origin, due to either low magnesium intake, low intestinal absorption of magnesium or derivation of extracellular magnesium toward bone, such as in bone reparation process after hyperparathyroidism surgery. Daily magnesium excretion higher than 2mmol/L concomitant to hypomagnesaemia indicates native or acquired renal loss of magnesium. Congenital renal and extra-renal losses of magnesium are mainly related to rare monogenic disease, and are inconstantly associated with a renal loss of sodium, potassium and calcium. Recent progress in the genetics of this rare diseases have greatly improved the knowledge about proteins involved in intestinal abortion, renal renal tubular re-absorption of magnesium and its regulations. Hypermagnesemia is a rarer metabolic disorder than hypomagnesemia (about 5% of hospitalized patients). Asymptomatic below 2mmol/L, it progressively alters neuromuscular transmission, autonomic sympathic activity and cardiac conduction, with vital risk above 7mol/L. It is due to acute magnesium input into extracellular volume most often associated with a decrease in glomerular filtration rate, limiting the high physiological ability to excrete magnesium input., (Copyright © 2012 Association Société de néphrologie. Published by Elsevier SAS. All rights reserved.)

The efficacy and safety of anti-infective treatments are associated with the drug blood concentration profile, which is directly correlated with a dosing adjustment to the individual patient's condition. Dosing adjustments to the renal function recommended in reference books are often imprecise and infrequently applied in clinical practice. The recent generalisation of the KDOQI (Kidney Disease Outcome Quality Initiative) staging of chronically impaired renal function represents an opportunity to review and refine the dosing recommendations in patients with renal insufficiency. The literature has been reviewed and compared to a predictive model of the fraction of drug cleared by the kidney based on the Dettli's principle. Revised drug dosing recommendations integrating these predictive parameters are proposed.

Familial juvenile hyperuricemic nephropathy is a rare autosomal dominant disease. It is characterized by abnormal handling of urate responsible for hyperuricaemia often complicated of gouty arthritis. Renal failure is due to tubulointerstitial nephritis. Ultrasonography sometimes finds renal cysts of variable size and number. Renal histology, although not specific, shows interstitial fibrosis, atrophic tubules, sometimes enlarged and with irregular membrane thickening. Renal failure progresses to end stage between 30 and 60 years of age. Allopurinol treatment is recommended at the early stages of the disease, its efficacy on slowing down the progression of the disease is however not proven. There is genetic heterogeneity in familial juvenile hyperuricemic nephropathy. Uromodulin encoding Tamm-Horsfall protein is the only gene to date identified, responsible in less than half of the families. The described mutations most often concern a cystein and are clustering in exon 4. These mutations result in abnormal retention of the protein in endoplasmic reticulum of Henle loop cells and in reduction of its urinary excretion. The pathophysiology of the disease is however still dubious. Indeed, Tamm-Horsfall protein functions are not well known (anti-infectious role, cristallisation inhibition, immunomodulating role). Knock-out mice do not develop renal phenotype but are more prone to E. coli urinary infections. Uromodulin gene mutations have also been described in medullary cystic kidney disease, an autosomal dominant tubulointerstitial nephropathy, considered at first as a distinct disorder. Genetic progress allowed us to consider familial juvenile hyperuricemic nephropathy and medullary cystic kidney disease as the two facets of a same disease, we should call uromodulin associated kidney diseases. At least two other genes have been implicated in similar clinical presentation: TCF2 and the gene encoding renin., (Copyright © 2011 Association Société de néphrologie. Published by Elsevier SAS. All rights reserved.)

Intravenous bisphosphonates or denosumab are a key component for the treatment of bone metastases. Their efficacy on the frequency and the number of skeletal events has been clearly shown. They also exhibit some variable activity on metastatic bone pain. Most often, the side effects of IV bisphosphonates are well-tolerated. However, new and more severe side effects have also been reported, with an increasing incidence. These toxicities regard the bone (osteonecrosis of the jaw) and the kidneys (acute renal failure) and are considered a class effect of bisphosphonates (varying by their potency) and prevention is mandatory. Recent data on denosumab have led authorities to suggest no need for renal monitoring in patients treated with this drug. However, as renal function changes are frequent in cancer patients, and have implications for many treatments, we suggest that calculated creatinine clearance should be regularly checked.

Background: The increased incidence of cancer in dialysis patients has been discussed since the mid-70s. Consequently, oncologists, nephrologists and pharmacists are increasingly facing challenging situations of cytotoxic drug handling in dialysis patients. In dialysis patients, two main issues must be considered. First, renal function of hemodialysis (HD) patients is no longer functional. Therefore, these patients may necessitate drug dosage reduction, namely drug prescription, must be cautiously checked before administration with appropriate dosage adjustment whenever necessary to ensure efficacy while avoiding overdosage and related side effects. Secondly, drug clearance by dialysis must be taken into account for appropriate chemotherapy timing in order to avoid drug removal, which may result in a loss of efficacy., Methods: We reviewed the international literature on the pharmacokinetics, efficacy, tolerance and dosage adjustment of anticancer drugs used on hemodialysis cancer patients, using the key words: kidney, renal, dialysis, hemodialysis, end-stage renal disease and the name of each drug., Results: Only case reports and small series were found. 57.1% of the drugs need dosage adjustment and 64.3% should be administered after the dialysis session., Conclusion: Cancer treatment in feasible in dialysis patients. Some drugs require dosage adaptation while others can be given as in patients with normal kidney function. These patients need coordinated care between oncologists, nephrologists and pharmacists to optimize drug delivery and logistics. Frailty scores, like in oncogeriatrics, should be built to optimally adapt cancer treatments in these dialysis patients.

Amongst numerous promising anticoagulant molecules, rivaroxaban (Xarelto(®)), dabigatran (Pradaxa(®)) and apixaban (Eliquis(®)) have been registered outside the USA in the prevention of thromboembolic events in patients undergoing total hip or knee prosthetic replacement. Rivaroxaban however has been granted authorisation by the FDA for the thromboprophylaxis after surgery for total hip or knee surgery. Dabigatran has been granted authorisation by the FDA in non-valvular atrial fibrillation (RE-LY trial) while rivaroxaban is expecting approval in this same indication (ROCKET trial). Phase III results in the treatment and in the secondary prevention of established venous thrombosis and pulmonary embolism are encouraging. These small molecules are obtained by chemical synthesis, their molecular weight is lower than 500 daltons. Many coagulation tests may be affected by these molecules. Those modifications should be known in order to avoid misinterpretation of the tests but could also be used to measure plasma concentrations of these products. The choice of a non specific global and readily available test has been documented (Quick time for rivaroxaban and aPTT for dabigatran). Anti-Xa (for rivaroxaban) and anti-IIa (for dabigatran) activities should however be preferred, expressed in ng/ml with calibrated plasmas (containing predetermined concentration of the tested drug). The half-life is around 8 to 12 hours, with a peak activity 2 to 4 hours after ingestion. Dabigatran is mainly eliminated via the kidney, hence requiring dose-adjustment in case of moderate renal insufficiency, and contra-indicated in case of severe renal insufficiency. Rivaroxaban being excreted via kidney and liver, some precautions should apply in case of liver insufficiency. No data are available in pregnancy or pediatrics, clinical trials are ongoing. There are few interactions with concomitant drugs, which should not be ignored. The short half-life of these new agents compensates for the lack of any specific antidote in many instances. Their oral administration, without the need for dose adjustment, and without requirement for a laboratory monitoring will increase their use in a large number of patients, in those indications for which an approval has been granted by health authorities., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

The interindividual variability in pharmacokinetics represents one of the factors involved in difference of both efficacy and toxicity of anticancer drugs prescribed to patients with the same cancer disease. The causes of pharmacokinetic interindividual variability are themselves divers. The impaired organic function corresponding either to liver or kidneys represents the major cause since any impaired function is systematically responsible of pharmacokinetic modifications, and due to the amplitude of these modifications. In this article, the clinically relevant pharmacokinetic parameters are shown. The methodologies used to study the pharmacokinetic variability due to impaired organic functions and to control them are detailed.

MicroRNAs (miRNAs) are an abundant class of small noncoding RNAs, evolutionarily conserved, that post-transcriptionnaly regulate gene expression by promoting degradation or repressing translation of the targetted messenger RNA. Recent data suggest the implication of miRNAs in renal development, and in renal diseases pathophysiology including fibrogenesis, regulation of innate and adaptive immunity, autoimmune diseases and acute rejection of the renal allograft. Herein, we review the implication of miRNAs in renal pathophysiology.

Calcium and phosphate play a key role in bone mineralization but have also many other physiological functions. The control of serum phosphate concentration is mandatory to avoid the occurrence of severe metabolic disorders, but is less tightly regulated than serum ionized calcium concentration, which is maintained in a very limited range thanks to parathyroid hormone (PTH) and the active vitamin D metabolite calcitriol. Any change in serum ionized calcium concentration is detected by the calcium sensing receptor (CaSR), a membranous protein located principally in the parathyroid glands and the kidney. A decrease in ionized calcium level inactivates the CaSR, thus stimulating PTH secretion. PTH in turn stimulates the release of calcium and phosphate from bone, renal calcium reabsorption and calcium and phosphate intestinal absorption by inducing renal calcitriol production. Moreover, PTH inhibits phosphate reabsorption in proximal tubular cells, thus contributing towards phosphate homeostasis. Fibroblast growth factor 23 (FGF23) is a circulating factor that decreases serum levels of inorganic phosphate by inhibiting renal phosphate reabsorption and calcitriol production and may have a great physiological role in phosphate homeostasis. Recently, vitamin D actions independent of calcium and phosphate homeostasis were discovered. Basal exploration of phosphocalcic metabolism abnormalities consists in measurement of serum calcium (ionized calcium if possible), phosphate, 25-hydroxy vitamine D and PTH and of 24 hours urinary calcium excretion as well as renal function. Hence, the understanding of physiopathological mechanisms has been improved by newly identified genetic disorders responsible for phophocalcic homeostasis disturbances., (Copyright © 2010 Association Société de néphrologie. Published by Elsevier SAS. All rights reserved.)

Parental imprinting and the type of the genetic alteration play a determinant role in the phenotype expression of GNAS locus associated to pseudohypoparathyroidism (PHP). This imprint is tissue-specific, mainly localized in the kidney and the thyroid. Only the maternal allele is expressed at this level. An alteration in the coding sequence of the gene leads to an haplo-insufficiency and a dysmorphic phenotype (Albright's syndrome). If the alteration is on the maternal allele, there is a hormonal resistance to the PTH at the kidney level and to the TSH at the thyroid level. The phenotype is known as a PHP1a. If the alteration is on the paternal allele, there are few clinical signs with no hormonal resistance and the phenotype is known as pseudo-pseudo-hypoparathyroidism (PPHP). Methylation anomalies of GNAS locus, in particular of exon 1A, are responsible for a lack of expression of Gαs at kidney and thyroid levels only. If these anomalies concern the maternal allele (the only one expressed) with a paternal pattern, there is no haplo-insufficiency and no dysmorphic syndrome. The hormonal resistance is yet again limited to PTH and TSH. The phenotype is known as PHP1b. In the familial forms, these methylation anomalies are associated with a deletion of the syntaxine 16 gene in the maternal allele. This gene contains probably the imprinting center of the locus., (Copyright © 2009. Published by Elsevier SAS.)

During pregnancy, the maternal, placental and fetal physiological characteristics constantly evolve and thereby constantly alter drug bioavailability in the mother and feto-placental unit. Gastric emptying time is increased and bowel movements are reduced. Distribution in the maternal body is mainly influenced by body mass variations, water content and fat stores. Metabolic capacity of the liver appears unchanged but renal clearance of drugs is gradually increased. The placental transfer of most drugs mainly consists of passive diffusion between the maternal and fetal circulations, along their respective concentration gradients. Only the free, unbound and non-ionized fraction of the drug readily crosses the membranes. Four anti-hypertensive drugs have been granted a license for the treatment of PE since the year 2000: these are Clonidine (Catapressan), Nicardipine (Loxen+), Labetalol (Trandate), Dihydralazine (Nepressol). Dihydralazine, Labetalol and Nicardipine are not contraindicated in the breast feeding mother. The administration of a long acting Benzodiazepine during pregnancy can lead to new born intoxication of variable severity and duration. These symptoms may precede a withdrawal syndrome (hyper-excitability, tremor, gastro-intestinal upset, such as diarrhea or vomiting). Breast feeding by mothers using benzodiazepines (Nitrazepam and Midazolam) is not recommended. In France, the use of low molecular weight heparins is not recommended during pregnancy whereas in the United States, they are recommended as a prophylactic measure. Their high molecular weight prevents their diffusion across the placental membrane and therefore prevents any fetal or neonatal risk. Bromocriptine is used as an inhibitor of lactation. During the post-partum period, serious accidents have been described: these consist of systemic hypertension, fits, infarcts (cardiac and neurological). It is contraindicated in case of systemic hypertension., (Copyright 2010 Elsevier Masson SAS. All rights reserved.)

Cadmium is a metallic impurity in various minerals. The two main cadmium exposure sources in general population are food and tobacco smoking. Its industrial exploitation has grown in the early twentieth century. Cadmium is used in accumulators or alkaline batteries (80%) and in pigments for paints or plastics (10%), in electrolytic process by deposit or by cadmium plating on metals or to reduce melting points (welding rods...). Cadmium is a cumulative toxic substance whose half-time for elimination is about 20 to 40 years and it is mainly stored in the liver and kidneys. Inhalation of cadmium oxide fumes may cause inhalation fevers or chemical pneumonitis. Cadmium chronic poisoning causes mainly renal tubulopathy and could be the cause of osteomalacia and diffuse osteoporosis. Cadmium is classified as certain carcinogen agent for humans by International Agency for Research on Cancer (IARC). The most relevant biological index exposure is the urinary cadmium. According to literature, no chelating agent can be still used in human cadmium poisonings. In France, some diseases caused by occupational exposure to cadmium may be compensated.

Association of paracetamol (PARA) and diclofenac (DiCF) is the aim of our study. 60 male rats "Albinos wistar" were treated by oral gavage (per os) during seven days. A control group was treated by mineral water (0+0) mg/kg and a second group was treated with only a toxic dose of 100 mg/kg of PARA (100+0). Remaining lots were treated with a combination of different toxic doses of PARA and a therapeutic dose of DiCF (15+3, 100+3, 200+3 and 400+3) mg/kg. Plasma concentration of amiotransferases (ASAT, ALAT), alkalines phosphatase (ALP), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione (GSH), glucose, cholesterol, creatinin, direct and total bilirubin, significantly varied in the treated rats regarding to the witness's rats. The toxicity of PARA revealed by a dose dependant blood increases of ASAT, ALAT, ALP, GPx, GR, glucose, creatinin, bilirubin, and by decreases of cholesterol concentration and tissue GSH in comparisons to controls. The depletion of GSH and the increase of the oxidative stress enzymes (GPx and GR) suggest a detoxification function of the glutathione system. The association (PARA + DiCF) revealed a protective effect, resulting in the increase of the concentrations of ASAT, ALAT, ALP, GPx, GR, bilirubin and the increase of GSH. Regarding to all these results, it has been suggested that DiCF has a protective action towards the toxic effects of PARA.

The doses of anticancer drugs are usually calculated according to the body surface area. This practice is based on the hypothesis that clearance is proportional to this morphologic parameter. That is rarely true, thus the pharmacodynamic effects (particularly haematological toxicity) are often better correlated with plasma drug concentrations than with doses. The elimination pathways of anticancer drugs will be presented, together with their main sources of interindividual variability. Methods of estimation of renal function will be discussed. These pharmacokinetic concepts allow understanding new alternative methods for individual dosing in oncology.

Renal allograft biopsies (n=34) of two different populations of patients according to the immunological risk (high versus low-risk) have been compared retrospectively. The presence of polymorphonuclear leukocytes in peritubular capillaries was more frequent in the high-risk group. The C4d staining was positive in 10% of the low-risk patients and in 50% of the high-risk patients (P=0.03). There were more early graft loss, renal infarctions, interstitial hemorrhage, severe glomerulitis, neutrophilic glomerulitis and Banff III grade rejection in the positive C4d group. In conclusion, half of the immunized patients had a humoral rejection, patients with a C4d positive rejection had more early graft loss and more severe histological lesions.

Effects of daily injections of lithium carbonate (20, 40 or 80 mg/kg body weight) during 14 and 28 days were investigated in Wistar mice. Attention was paid (1) to changes in concentrations of lithium, creatinine and urea in serum, (2) to level of oxidative stress by measuring lipids peroxidation level and catalase, superoxide-dismutase and glutathione-peroxidase activities, and (3) to changes in the histological structure of brain. The first intraperitoneal injection was followed by a transitory peak of lithium in the blood, reaching 0.25 mM and 1.1 mM and disappearing 6 and 12 h later for the 20 and 80 mg/kg doses, respectively. From the first to the last day of treatment, lithium concentrations in the blood, measured 12 h after the injections, increased from 0 to 0.11 mM (20 mg/kg dose) or 0.25 mM (80 mg/kg dose). The 80 mg/kg treatment induced a renal insufficiency evidenced by an increase of blood creatinine and urea levels. Lithium treatment was found to trigger an oxidative stress in kidney, but not in brain. In kidney, the lipid peroxidation level (TBARS) and the superoxide dismutase and catalase activities were increased. No change in glutathione peroxidase activity was detected. Histology of the brain cortex revealed interesting modifications: thicker neuronal cells and a denser network of dendrites, as compared to controls.

Cystatin C is a protein freely filtered in the renal glomerulus, then reabsorbed and completely metabolised within the tubular cells. The possibility to predict the clearance of compounds eliminated by the kidneys (and then to control their interindividual variability) was evaluated for two cytotoxic drugs (carboplatin and topotecan) in adults and EDTA (ethylene diamine tetraacetic acid), a compound used to determine the glomerular filtration rate in children. The population pharmacokinetic approach based on NONMEM program was used. For each of the three compounds, the cystatin C serum level was better predictive of clearance than that of creatinine. Moreover, for carboplatin and EDTA, the best equation between clearance and patients' characteristics included both cystatin C and creatinine level. A generalisation of cystatin C assay would contribute to standardise the clinical practices in Oncology.

Vitamin D is well known as a hormone involved in mineral metabolism and bone growth. Conversion into the active metabolite 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) from the precursor is effected by cytochrome P450 enzymes in the liver (CYP27A1 and CYP2R1) and the kidney (CYP27B1). CYP27A1 has been shown to be transcriptionally regulated by nuclear receptors (PPARalpha, gamma, HNF-4alpha and SHP) which are ligand-dependent transcription factors. CYP27B1 is tightly regulated by the plasma levels of calcium, phosphate, parathyroid hormone (PTH) and 1,25(OH)2D3 itself. In vitamin D target organs, inactivation of vitamin D is attributed to CYP24A1 which is transcriptionally induced by 1,25(OH)2D3 whose action is mediated by binding to its cognate nuclear receptor, the vitamin D receptor (VDR). Diseases associated to Vitamin D deficiency (rickets in children, and osteomalacia or osteoporosis in adults) and autosomal recessive forms of inherited rickets illustrate the key role of vitamin D in calcium homeostasis and bone metabolism. Recently, discovery of 1,25(OH)2D3 new biological actions that include antiproliferative, prodifferentiating effect on many cell types and immunoregulatory properties creates a growing interest for this vitamin. In this way, a best understanding of various actors implicated in vitamin D metabolism and its regulation is of a major importance to optimise the use of vitamin D in disease prevention.

Adverse drug effects are more frequent in elderly patients, especially with drugs that have small safety margins. This is the case of many cardiovascular drugs. Patients who are frail, owing to their age and their psychomotor, nutritional and social stratus, are particularly at risk. Two pharmacokinetic factors appear to be of major concern, namely the age-related decrease renal function and changes in drug metabolism and distribution. Renal function is probably the single factor most responsible for altered drug levels in the elderly. The normal age-related decrease in creatinine clearance can lead to the accumulation of drugs that are normally excreted by the kidneys without being inactivated Dose adjustment of such drugs is usually based on the Cockcroft-Gault formula of creatinine clearance. Changes in hepatic metabolism and drug distribution are less commonly taken into account. The avoidance of drug toxicity requires familiarity with the medications prescribed and particular vigilance for signs of adverse effects.

The frequency of hypercalciuria is increasing in western countries with an incidence of nephrolithiasis which can reach 13%. Hypercalciuria appears as an alteration of the calcium transport system (kidney, bowel, bone) which is regulated by calcitriol and parathormone. The aim of this review was to screen etiologies of hypercalciuria taking into account recent genetic advances (calcium epithelial channel and calcium sensing receptor). Hypercalciuria may be favored by nutritional causes (diet rich in calcium, sodium, carbohydrates, proteins, poor in phosphates and potassium). It may also be related to an increase in calcium absorption (vitamin D excess, primary hyperparathyroidism, sarcoidosis, lymphoma, estrogens, and certain genetic causes), an increase in osteoresorption (bone metastasis, myeloma, Paget, hyperthyroidism, immobilization, hypercortisolism and corticosteroid therapy), or a decrease of kidney tubular resorption (diuretics, Cacci and Ricci, acromegally, Bartter, familial dominant hypocalcemia, Fanconi, Dent, familial hypomagnesemia-hypercalciuria syndrome, type 1 distal tubular acidosis, pseudohypoaldosteronism, diabetes). If no cause is identified, persistence of hypercalciuria after instituting a correct diet is defined as idiopathic hypercalciuria. Treatment of the cause is essential in secondary hypercalciuria, in addition to diet (low sodium intake, normocalcic diet, hydration), associated with thiazide diuretics and biphosphonates if necessary.

Adefovir is transported by the organic anion transporter (OAT1) and the multidrug resistant protein (MRP2, 4 and 5). We studied adefovir clearance in rat after inhibition of transporters by probenecid and in TR- rats, in which MRP2 is lacking. After treatment by probenecid or placebo, pharmacokinetics of adefovir 10 mg/kg was studied via population modeling (NONMEM). The fraction of drug excreted in the urine was low. Renal clearance of adefovir was significantly lower (P < 0.05) in probenecid TR- rats (0.03 +/- 0.02 l/hour) than in normal control (0.09 +/- 0.05 l/hour), in normal probenecid (0.10 +/- 0.07 l/hour) and in TR- control rats (0.13 +/- 0.07 l/hour). In vivo in rats MRP2 mutation alone did not affect adefovir clearance suggesting that MRP2 does not play a critical role in the secretion of adefovir. Additional pharmacological inhibition of transporters decreased renal clearance, which may reflect inhibition of compensating transport mechanisms activated when MRP2 is lacking.

In France, psychotropic drugs may be classified in four categories according to their official data. The first category corresponds to psychotropic drugs with an approved indication available in paediatry. Theyare old agents (e.g. haloperidol, amitriptyline, benzodiazepines...) with the exception of methylphenidate (hyperactivity). The second one corresponds to pharmacological agents approved for some indications obtained with adults but not for a1l (i.e. restricted indication: e.g. sertraline approved in paediatry only for OCD but not for depression, risperidone approved only for the treatment of disruptive behaviors in children with subaverage IQs). For the third category, the psychotropic agent is either contraindicated or unadvised under the age of 15 or 18 years, by lack of data (e.g. most of SSRI or atypical antipsychotic drugs). For the last category, official data available in brief summaries offer no information on paediatric use and consequently their administration does not appear possible. Up to now, no approved use has been delivered to injection route (IM or IV) in France, except for an IM formulation of zuclopenthixol. Prescribing psychotropic drug has to respect good practices including close psychological and somatic monitoring that associates the young patient and his relative (psycho-education program). Particular key-points should be taken into consideration (i.e. pharmacokinetic and physiological specificities, risk of false passage under the age of 6 years with capsules or tablets, presence of alcohol in some oral solution or bitter aroma...). Beside these official data, many studies have been published but must be carefully interpreted according to their level of pertinence. Meta-analysis gather all randomised controlled trials published or not, analyse their specific pertinence and thus provide clinically relevant elements. Randomised controlled trials present clinical interest but key-points in study design must be checked (e.g. number of patients, inclusion and exclusion criteria, length of the study and clinical relevance of clinical scales...). Other studies like open trials or clinical cases do not offersufficient guarantees. Some randomised controlled trials of clinical relevance have been carried out in this population with new pharmacological classes (eg SSRI, atypical antipsychotic drugs) and may lead to extended indications in children and adolescents. According to bibliographic and official data, the main criteria in the prescribing choice may take into consideration the following sis stressing a poor benefit/risk ratio. SSRI may offer better prospects but their use has not been approved in this indication, until now. In OCD, sertraline shows great interest to enhance clinical response and represents the molecule of reference. No drug has been approved for mood disorders in children or adolescent, in France, contrary to USA where lithium can be administered over the age of 12 years. In addition, antiepileptic drugs like carbamazepine or divalproate have conducted to clinical improvement in some studies. Benzodiazepines, hydroxyzine and meprobamate use should be strictly restricted in case of anxiety symptoms but are the only agents approved in this indication despise promising results obtained with SSRI. Transitory insomnia may take advantage of alimemazine prescription (approved use over the age of 36 months). Some typical neuroleptics are indicated in tics or in behaviour disorders associated to autism or related syndromes but present clinical limitations and poor tolerability. Promising clinical trials (randomised or not) have been conducted with new atypical antipsychotic drugs like risperidone. In conclusion, present data available for paediatric use of psychotropic agents emphasizes that safety and effectiveness are not always well established in particular for the treatment of chronic disorders (long term tolerability assessment). Moreover, studies should be carried out to specify factors promoting adherence and quality of life for this young population in order to optimise clinical benefit of drug prescription.

Phosphorus is mainly present in the serum as phosphate which is the principal intracellular anion, essential for the organism, in particular through its role in the production of ATP. In plasma, only inorganic phosphorus (Pi) is measured. In this article, we will review new information about the regulation of Pi at the intestinal, osseous and mainly renal levels. The various cotransporters sodium-phosphorus (Na-Pi) will also be examined and the molecular regulation mechanisms approached. Finally, illustration of Pi physiology will be given through various clinical examples.

Magnesium (Mg) therapy is often proposed against stress and to correct asthenia. Thus our aim has been to review the role of Mg, the mechanisms of its homeostasis before detailing the clinical presentations and etiologies of hypo- and hypermagnesemia and their exploration. Hypomagnesemia frequently occurs but is clinically rarely recognized without biological serum ionic determinations because causing atypical signs miming those of other ion deficiencies. Hypermagnesemia is uncommon but often occurs in the presence of renal insufficiency especially with excess of Mg administration.

The authors report the case of an 18-year-old man with polytrauma, who died at the third day of its accident from brain death and who presented during his stay in the intensive care unit, a deep hypophosphatemia. Two physiopathologic mechanisms were presumed: increase of renal losses and intracellular transfer of phosphorus. Consequences, as well as the indications and the therapeutic modalities of hypophosphatemia are discussed.

In France, 45,000 patients are treated by hemodialysis and/or transplantation for chronic renal failure. Every year 7,000 new patients need such a therapeutic approach. The estimated cost of this pathology is about 1% of the total amount of the budget of social security, even though the number of patients is limited. Some treatments were shown to be effective in improving the progression of chronic renal failure, as for example the anti-hypertensive therapy and the adequate treatment of diabetes mellitus. Collagen deposition in each segment of the kidney, mainly in the interstitium, plays a pivotal role in the progression of renal deficiency in chronic renal failure. In order to ameliorate the progression renal failure it would be essential to know: 1) the different types of collagen deposit; 2) the proteinase/antiproteinase systems involved in the remodelling of the extracellular matrix (serine-protease, metallo-protease and their inhibitors); 3) the autocrine/paracrine effects of proteases and of growth factors on collagen synthesis. The more precise the knowledge of these factors, the more useful will be new pharmacological-, gene- or cellular therapies for limiting the progression of chronic renal failure.

ANTIINFLAMMATORY DRUGS: Non-steroidal antiinflammatory drugs (NSAID) constitute one of the most widely prescribed drug classes. Selective inhibitors of cyclooxygenase type 2 (Cox-2) can have antiinflammatory and antialgesic activities without affecting prostaglandin synthesis at sites where classical NSAID have known toxicity. This fact has led to the development of celebrex and rofecoxib, the leading selective inhibitors of Cox-2. We review here the renal effects of steroidal antiinflammatory drugs. RENAL EFFECTS OF NSAID: The renal effects of NSAID are, in decreasing order: electrolyte imbalance (hyperkaliemia, edema, hypertension), acute renal failure, nephrotic syndrome associated with interstitial nephropathy, papillary necrosis. Electrolyte disorders and acute renal failure are observed more frequently in patients with risk factors. INTRARENAL LOCALIZATION OF CYCLOOXYGENASE: Cox-1 is present in endothelial and smooth muscle cells of pre- and postglomerular vessels as well as in the cortex, the medullary tubes and in interstitial cells. Cox-2 expression has been identified in the interstitium, medullary tubes and intercalate cells, and in the deep medulla. The regulatory role of Cox-2 on renin production has been demonstrated in the macula densa. RENAL EFFECTS OF COX-2 INHIBITORS: Several studies have demonstrated that Cox-2 inhibitors inhibit prostaglandin synthesis much like conventional NSAID. The long-term effects of selective inhibitors of Cox-2 on blood pressure, edema, kaliemia and renal function have also been described. All these studies point to the strictly identical renal effects of these new drugs and conventional NSAID.

A mitochondrial dysfunction has been suggested to explain chronic renal toxicity observed in ciclosporine A therapy. Our study has investigated whether trimetazidine allows inhibition of mitochondrial alteration induced by ciclosporine A. Oxidative phosphorylation was measured by polarography, calcium fluxes by a specific calcium electrode and the mitochondrial swelling by determination of the optical density at 520 nm, using a spectrophotometer. The ciclosporine A effect on the respiratory control was fully inhibited by trimetazidine (EC50 5.10 x 10(-7) M; Emax 11 per cent). Trimetazidine also inhibited the ciclosporine effects on calcium fluxes, i.e. calcium accumulation into the matrix and delay of efflux. Trimetazidine allows a decrease of mitochondrial dysfunction induced by ciclosporine A.

The three platinum derivatives currently available share many pharmacokinetic and pharmacodynamic (PK-PD) properties but present also some distinct characteristics, due to their structural differences. They result in different systemic PK-PD and metabolic behaviour and toxicity profile. Oxaliplatin is quickly transformed into dach-platinum, the active metabolite, by loosing oxalate chain. Eighty to eighty-eight per cent of platinum are bound to proteins, as for cisplatin, whereas carboplatin is less reactive. Cisplatin and oxaliplatin active metabolites, i.e. monoaquo platin and dach-platin quickly react with small proteins with sulfhydryl groups, such as glutathione, cysteine and methionine, and then with high molecular weight proteins, such as albumin and gammaglobulins through covalent link. Thus, their terminal half lives are long, about ten days, but no platinum accumulation has been reported in plasma with oxaliplatin, whereas after cisplatin administration, both total and ultrafiltrable platinum progressively accumulate in plasma. This difference may play a role in the lack of oxaliplatin nephrotoxicity and its more delayed and reversible neurotoxicity. On the other hand, carboplatin is more stable, less bound to proteins and is largely excreted inchanged in urine. This can explain that it passes more easily through the blood brain barrier. Erythrocytes represent an important deep compartment, especially for oxaliplatin, a little bit less for cisplatin. Oxaliplatin is trapped in erythrocytes through a covalent binding to globin. There, its half life is identical to that of erythrocytes. According to certain authors, this trapping would be involved in the incidence of anemia. On the contrary, carboplatin is quickly extruded from erythrocytes. The three derivatives kinetics in plasma present a wide interindividual variability, resulting in differences in term of toxicity and efficacy. For the three of them, plasma clearance is correlated to creatinine clearance, but only carboplatin dosage can be individually adjusted, based on creatinine clearance measurement, thanks to its simple renal excretion, due to exclusive glomerular filtration, and after Calvert's, Egorin's and Chatelut's population kinetics studies. Cisplatin renal excretion is more complex, combining reabsorption and secretion processes. Therefore, individual dosage adjustment needs platinum concentration measurement in plasma, but there is no general agreement on the platinum species to measure, ultrafiltrable or bound. Oxaliplatin is too recent in clinical practice and still lacks of PK-PD data. These characteristics can help us for a better knowledge of the three platinum derivatives clinical properties, both in term of kinetics, behaviour and toxicity.

Interest has recently risen regarding thiamine deficiency in patients with cardiac deficiency who are receiving long-term diuretic therapy. Thiamine deficiency can lead biventricular myocardial failure (cardiac beriberi), and treatment consists of thiamine administration. Studies have shown that long-term furosemide use may be associated with thiamine deficiency through urinary loss, contributing to cardiac insufficiency in patients with congestive heart failure. Thiamine supplementation could improved left ventricular function. However, the results of those studies are controversial, and none study have till proved the clinical impact of a systematic administration of thiamine in a cohort of patients with cardiac insufficiency. To date, and waiting for available literature, thiamine administration should be consider in patients at risk for thiamine deficiency (elderly, malnourished, alcoholic), and in patients receiving very large doses of diuretics.